A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma.

OBJECTIVE: Ipilimumab is a fully human, anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. METHODS: Chemotherapy-naïve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m(2)/day. The primary efficacy endpoint was objective response rate. RESULTS: Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8-30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7-18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2-18.8) and 11.4 months (95% CI, 6.1-15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively. CONCLUSION: Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.

Improved survival with ipilimumab in patients with metastatic melanoma.

BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

Treatment with monoclonal antibodies against Clostridium difficile toxins.

BACKGROUND: New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection. METHODS: We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo. RESULTS: Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P<0.001). The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P=0.006). The mean duration of the initial hospitalization for inpatients did not differ significantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P=0.09). CONCLUSIONS: The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298.)

Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.

PURPOSE: Immunotherapeutic agents produce antitumor effects by inducing cancer-specific immune responses or by modifying native immune processes. Resulting clinical response patterns extend beyond those of cytotoxic agents and can manifest after an initial increase in tumor burden or the appearance of new lesions (progressive disease). Response Evaluation Criteria in Solid Tumors or WHO criteria, designed to detect early effects of cytotoxic agents, may not provide a complete assessment of immunotherapeutic agents. Novel criteria for the evaluation of antitumor responses with immunotherapeutic agents are required. EXPERIMENTAL DESIGN: The phase II clinical trial program with ipilimumab, an antibody that blocks CTL antigen-4, represents the most comprehensive data set available to date for an immunotherapeutic agent. Novel immune therapy response criteria proposed, based on the shared experience from community workshops and several investigators, were evaluated using data from ipilimumab phase II clinical trials in patients with advanced melanoma. RESULTS: Ipilimumab monotherapy resulted in four distinct response patterns: (a) shrinkage in baseline lesions, without new lesions; (b) durable stable disease (in some patients followed by a slow, steady decline in total tumor burden); (c) response after an increase in total tumor burden; and (d) response in the presence of new lesions. All patterns were associated with favorable survival. CONCLUSION: Systematic criteria, designated immune-related response criteria, were defined in an attempt to capture additional response patterns observed with immune therapy in advanced melanoma beyond those described by Response Evaluation Criteria in Solid Tumors or WHO criteria. Further prospective evaluations of the immune-related response criteria, particularly their association with overall survival, are warranted.

Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade.

PURPOSE: CTL-associated antigen 4 (CTLA-4) can inhibit T-cell activation and helps maintain peripheral self-tolerance. Previously, we showed immune-related adverse events (IRAE) and objective, durable clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade. We have now treated 139 patients in two trials and have sufficient follow-up to examine factors associated with clinical response. EXPERIMENTAL DESIGN: A total of 139 patients with metastatic melanoma were treated: 54 patients received ipilimumab in conjunction with peptide vaccinations and 85 patients were treated with intra-patient dose escalation of ipilimumab and randomized to receive peptides in accordance with HLA-A*0201 status. RESULTS: Three patients achieved complete responses (CR; ongoing at 29+, 52+, and 53+ months); an additional 20 patients achieved partial responses (PR) for an overall objective response rate of 17%. The majority of patients (62%, 86 of 139) developed some form of IRAE, which was associated with a greater probability of objective antitumor response (P = 0.0004); all patients with CR had more severe IRAEs. Prior therapy with IFNalpha-2b was a negative prognostic factor, whereas prior high-dose interleukin-2 did not significantly affect the probability of response. There were no significant differences in the rate of clinical response or development of IRAEs between the two trials. The duration of tumor response was not affected by the use of high-dose steroids for abrogation of treatment-related toxicities (P = 0.23). There were no treatment-related deaths. CONCLUSION: In patients with metastatic melanoma, ipilimumab can induce durable objective clinical responses, which are related to the induction of IRAEs.

A clinical development paradigm for cancer vaccines and related biologics.

Therapeutic cancer vaccines are a heterogeneous group of complex biologics with distinctly different clinical characteristics than cytotoxic agents. The current clinical development paradigm used for oncology drug development is based on criteria developed for cytotoxic agents. More flexible and focused developmental guidelines are needed to address the unique characteristics of therapeutic cancer vaccines. Over the course of 1 year, the Cancer Vaccine Clinical Trial Working Group, representing academia and the pharmaceutical and biotechnology industries with participation from the US Food and Drug Administration, defined in a consensus process the cornerstones of a new clinical development paradigm for cancer vaccines and related biologics. Four major topics were addressed: (1) end points for clinical trials, (2) trial designs and statistical methods, (3) technical and developmental challenges, and (4) combination therapy. The proposed paradigm suggests therapeutic cancer vaccines to be investigated in 2 general types of clinical studies: proof-of-principle trials and efficacy trials. Proof-of-principle trials, which introduce a novel cancer vaccine into humans, should include a minimum of 20 or more patients in a homogenous, well-defined population in an adjuvant setting or without rapidly progressive disease in a metastatic setting to allow vaccines adequate time to induce biologic activity and should incorporate immune and molecular markers. Objectives should include initiation of a safety database, determination of dose and schedule, and demonstration of biologic activity as proof-of-principle. Biologic activity is defined as any effect of the vaccine on the target disease or host immune system using biologic markers as study end points, for example, clinical, molecular, or immune response. Immune response is demonstrated if determined in 2 separate, established and reproducible assays at 2 consecutive follow-up time points after the baseline assessment. If proof-of-principle trials show such immune response, or other biologic or clinical activity, efficacy trials may be initiated. If none of these end points is met, the clinical development plan should be reevaluated to decide if further development is warranted. Efficacy trials formally establish clinical benefit either directly or through a surrogate and are encouraged to be randomized studies. This is in contrast to single-arm phase 2 trials used for cytotoxic agents, which often use tumor response rate as the primary end point and historical controls as a comparator. Efficacy trials may use prospectively planned adaptive designs to expand from randomized phase 2 into phase 3 studies if well-defined trigger-point criteria are met, but the cost of incorporating such design elements should be carefully evaluated. Efficacy trials can also be exploratory randomized phase 2 trials or conventional phase 3 trials. In addition, conventional clinical end points can be adjusted to account for biologic features of cancer vaccines. The concept of efficacy trials allows for an early assessment of vaccine efficacy based on credible prospective data. This 2-phase developmental paradigm supports a more flexible, expeditious, and focused clinical developmental process with early and informed decision making. In addition, this report addresses clinical development challenges and issues for combination therapies.

Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma.

PURPOSE: Nineteen patients with high-risk resected stage III and IV melanoma were immunized with three tumor antigen epitope peptides from gp100, MART-1, and tyrosinase emulsified with adjuvant Montanide ISA 51 and received a fully human anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody MDX-010. Each of three cohorts received escalating doses of antibody with vaccine primarily to evaluate the toxicities and maximum-tolerated dose (MTD) of MDX-010 with vaccine. MDX-010 pharmacokinetics and immune responses were secondary end points. PATIENTS AND METHODS: Peptide immunizations with MDX-010 were administered every 4 weeks for 6 months and then every 12 weeks for 6 months. A leukapheresis to obtain peripheral-blood mononuclear cells for immune analyses was performed before treatment and after the sixth vaccination. Patients were observed until relapse. RESULTS: Grade 3 gastrointestinal (GI) toxicity (diarrhea or abdominal pain) was observed in three patients in the highest dose cohort and one in the middle dose cohort who seemed to be autoimmune. That defined the MTD with vaccine on this schedule at 1 mg/kg. Of eight patients with evidence of autoimmunity, three have experienced disease relapse. Of 11 patients without autoimmune symptoms, nine have experienced disease relapse. Significant immune responses were measured by tetramer and enzyme-linked immunospot assays against gp100 and MART-1. CONCLUSION: Dose-related autoimmune adverse events, predominantly skin and GI toxicities, were reversible. Patients mounted an antigen-specific immune response to a peptide vaccine when combined with a human anti-CTLA-4 antibody.